Pore-forming toxins (PFTs) are abundant bacterial virulence factors that play a role in infections by numerous problematic pathogens and are potential targets in the search for novel antimicrobial therapeutics. PFTs perforate host cell membranes, allowing bacteria to evade the immune system and spread within the host. Host cells in turn employ defense pathways to survive and repair their cell membranes. Besides disabling PFT function, PFT-targeting strategies may include the priming or boosting of host defenses. Activity and expression of NR4A-family orphan nuclear receptors, which we have identified as novel PFT defense factors, can be manipulated in vitro and in vivo by small compounds. We propose two specific aims directed at elucidating the molecular mechanisms of how NR4As defend against PFTs and intact pathogens using multiple model systems and at applying this new knowledge as a new therapeutic strategy for identifying small compounds to treat and prevent important infectious diseases.